This application is a national stage filing under 35 U.S.C. xc2xa7371 of PCT/EP99/05484, filed Jul. 27, 1999.
The present invention relates to a compound with antibiotic activity, which is useful in the treatment of infectious diseases, and more particularly relates to the compound of formula 
and to pharmaceutically acceptable salts thereof and pharmaceutical compositions containing it as active principle.
International patent application WO 96/18633 in the name of the Applicant discloses compounds with antibiotic activity, having the following general formula: 
in which
A is a phenyl or a 5- or 6-membered heterocycle containing one or more hetero atoms chosen from nitrogen, oxygen and sulphur, optionally substituted with 1 to 3 groups, which are the same or different and are chosen from linear or branched C1-C4 alkyl or alkoxy groups, C1-C2 cycloalkene dioxy groups, C1-C4 alkyl sulphonyl groups and phenyl, phenoxy, hydroxyl, carboxyl, nitro, halo and trifluoromethyl groups; R1 and R2 are the same or different hydrogen atom or linear or branched C1-C4 alkyl group; n is 1 or 2; m is an integer from 1 to 8; r is an integer from 2 to 6; R3 is a hydrogen atom or a methyl group.
We have now found that one of the compounds of general formula (I), but not given as an example in the above-mentioned international patent application, has a particularly broad spectrum of activity and a long duration of action, thereby making it extremely useful in antibiotic therapy.
It is an object of the present invention to provide a compound of formula 
and pharmaceutically acceptable salts thereof.
Examples of pharmaceutically acceptable salts of compound A are salts with organic or inorganic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid, sulphuric acid, phosphoric acid, acetic acid, tartaric acid, citric acid, benzoic acid, succinic acid and glutaric acid.
The preferred salt is the dihydrochloride.
Compound A of the present invention can be prepared by the synthetic methods already described in patent application WO 96/18633.
In particular, the synthesis of compound A is carried out according to the synthetic scheme given below. 
in which
Z and Z1, the same or different, represent a protecting group;
R represents a methyl or p-tolyl group.
The synthesis involves oxidation of the appropriately protected aminohexanol (1) with the corresponding aldehyde by treatment with an oxidizing agent, preferably sodium hypochlorite.
Condensation of the aldehyde (2) with 2-aminoethanol and subsequent reduction of the intermediate imine, preferably with NaBH4, gives the compound (3).
After also protecting the second amino group, the compound (4) is treated with mesyl or tolyl chloride to activate the OH group and allow the subsequent condensation of the activated compound (5) with erythromycin A oxime.
Removal of the protecting groups from the compound (6) gives the amino derivative (7), from which compound A of the present invention is prepared by treatment with the aldehyde of formula 
followed by reduction of the intermediate imine.
Compound A of the present invention has a broad spectrum of activity in vitro with respect to Gram-positive and Gram-negative microorganisms (Example 7).
This activity is greater than that of azithromycin on strains of Streptococcus pneumoniae and Streptococcus pyogenes with erythromycin resistance of inducible type.
However, the property which predominantly differentiates the compound of the present invention from the reference macrolides and also from the compounds of the same class described in the above-mentioned patent application WO 96/18633 is the appreciable duration of action in vivo. Specifically, as reported in Example 8, the therapeutic efficacy of compound A was compared with that of two reference macrolides (clarithromycin and azithromycin) and with that of two compounds described in WO 96/18633 which displayed an excellent activity profile both in vitro and in vivo (compounds 23 and 29 of WO 96/18633).
From the comparison, it is clear that clarithromycin and compound 29 lose most of their efficacy when administered 24 hours before the infection. Compound 23 and azithromycin also lose most of their efficacy 48 and 72 hours, respectively, after administration, while compound A of the present invention is still effective 72 hours after administration.
This particularly prolonged therapeutic efficacy significantly distinguishes compound A from the other reference macrolides, including the structurally related macrolides described in the oft above-mentioned patent application WO 96/18633.
The advantage of prolonged therapeutic efficacy is clear to those skilled in the art, since, from a practical point of view, it allows the dose of antibiotic to be reduced significantly and/or allows the interval between consecutive administrations to be increased, for example going from a prescription plan which involves two dosage intakes per day to a plan which involves only one dosage intake per day.
Compound A can be used in human and veterinary therapy.
For use in therapy, compound A can be used in a pharmaceutical form which is suitable for oral or parenteral administration.
It is therefore a further object of the present invention to provide a pharmaceutical composition containing a therapeutically effective amount of compound A or of a salt thereof, mixed with a pharmaceutically acceptable vehicle.
For the treatment of specific infections, compound A may also be combined with a therapeutically effective amount of another active principle.